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ISSN 2470-1025 SciForschenOpen HUB for Scientific Research Autoimmune and Infectious : Open Access Mini Review Volume: 2.3 Open Access

Received date: 25 Apr 2016; Accepted date: 09 (CMV) : A Role in the May 2016; Published date: 13 May 2016. Pathogenesis of Systemic Lupus Erythematosis Citation: Dosanjh A (2016) Cytomegalovirus (CMV) Infection: A Role in the Pathogenesis of Systemic (SLE) Lupus Erythematosis (SLE). Autoimmun Infec Dis 2(3): doi http://dx.doi.org/10.16966/2470-1025.115 Amrita Dosanjh* Copyright: © 2016 Dosanjh A. This is an open- Department of Pediatrics, University of California, Medical Center, San Diego, USA access article distributed under the terms of the Creative Commons Attribution License, *Corresponding author: Amrita Dosanjh MD, Pediatrics Respiratory, San Diego, California, which permits unrestricted use, distribution, and USA, Tel: +858 442 6146; E-mail: [email protected] reproduction in any medium, provided the original author and source are credited.

Abstract Autoimmune Diseases and in particular Systemic Lupus Erythematosis (SLE) are associated with responses to viral antigenemia. The mechanisms by which the and autoimmune are related include disease activation, mitigation and susceptibility of the host to the viral infection during exacerbations of autoimmune disease. This paper will review the cellular, molecular and disease associations between SLE and Cytomegalovirus infection.

Keywords: Systemic lupus erythematosis; Autoimmune disease; Viral infection

Introduction [7]. The immune profile among seropositive CMV autoimmune disease patients includes the proliferation of CD4+/CD28 null T cells. CD4+ CD28 , like other microbial agents may be integral triggering factors null population is three fold higher among CMV positive rheumatoid in the development of autoimmune disease. Many specific viruses have arthritis patients compared with healthy CMV positive patients [8]. This been implicated in the modulation of local and systemic environmental increase may be a marker for disease pathogenesis and progression. A factors that lead to the formulation of organ specific and circulating auto- previous study has shown that CMV specific CD4+CD 28 null cells are . Direct infection may activate an immune response by cross regulatory T cells [9]. reaction between carbohydrate, proteins, peptides or nucleic acids of the and the host’s molecular structural receptors [1,2]. Cytomegalovirus and Human Disease Viruses with pathogen specific epitopes with similarity to the host Human cytomegalovirus (CMV) is a member of the might activate auto reactive , which is termed molecular family. Compared to other members of the same viral family, CMV has mimicry. Transfer of viral specific epitopes to the host then initiates the the most genomic potential to modify the innate and adaptive immunity process of disease pathogenesis [3]. of the host. CMV is able to infect a multitude of cell types, including endothelial, epithelial, fibroblast cells and immune effector cells such as Mitigation of the autoimmune process by viral can also dendritic cells and monocytes/macrophages [10]. CMV infection may occur, particularly if there is repeated infection by the same viral strain. take many forms including primary infection, endogenous infection, or Viruses can attract potentially injurious T cells towards the infection by exogenous reinfection. Latent infection and persistent infection of the release of chemokines, which decreases the likelihood of autoantibody host may occur and causes activation of the immune system. production. T regulatory cells(TREG cells) when activated, may help to lessen the autoimmune processes [4]. CMV Clinical Infection Genetic Predisposition The manifestations of CMV vary from an asymptomatic state or mild respiratory infection to a potentially fatal multi-organ system Other lines of evidence suggest that genetic haplotype influences infection. CMV infection most often will initially present in childhood initiation of autoimmunity following a viral infection. The HLA D3 as a mild illness. In neonates, of the infection may be acquired in utero, haplotype and multiple genes, such as the STAT4 and APOA2 gene, and results in a multi-system disease with liver involvement, purpura, have been implicated as susceptibility factors [5,6]. The response to viral hepatosplenomegaly, and sensorineural hearing loss. In disease and the host’s genetic susceptibility to disease are both important older children and adults, CMV may be more prolonged and presents regulatory factors. The timing, cumulative viral disease burden, degree with and mild [10]. of inflammation, type of virus and its particular strain are bidirectional Autoimmunity and CMV Infection factors which can either induce or lessen the course of autoimmune disease. Multiple pathways in pathogenesis Specific epitope targeted expansion of CD8+ T cells,in response to Autoimmune responses are one result of defective tolerance. The CMV is not typical of other viral infections. CMV has been associated factors involved in triggering autoimmune responses are infection, genetic with many autoimmune diseases, and there has been a higher prevalence predisposition, immunologic, hormonal, psychological, emotional and of autoimmune disease among patients with CMV infection described external environmental conditions [10,11].

Copyright: © 2016 Dosanjh A. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

SciForschenOpen HUB for Scientific Research Open Access In general, there are multiple molecular mechanisms linking infections 1.03% in the control group ( p<0.001). The clinical disease activity score or to the development of autoimmune disease. Among these are that SLEDAI was significantly higher in patients positive for both anti-CMV infections can trigger or exacerbate autoimmune disease. The lifelong IGM and IgG compared to the patients with negative CMV IgM levels cumulative effects of multiple infections and immune dysregulation (11.4+/-6.77 compared with 3.87+/-3.36, p=0.012). In a multi-center may also be responsible for subsequent disease. Genetic predisposition retrospective survey of rheumatic diseases, there were 151 patients with to autoimmune disease and its influence on host responses leading to CMV infection. SLE was ther most commonly diagnosed ( n=74,50%), autoimmune disease is a key differentiating factor in determining which CMV associated rheumatic disease [15]. infected patients develop autoimmune responses. One example of genetic The mechanistic links between CMV reactivation and SLE flare up is determination of response to and susceptibility to autoimmune still unclear. There are several proposed mechanisms including i) SLE can disease are genetic variations in toll like receptors such as TLR3,7 and 9 lead to CMV reactivation, ii) SLE immunosuppressive therapy predisposes which may predispose to autoimmune disease [12]. to CMV, iii) CMV reactivation leads to an SLE flare. The support for the Induction of the production of autoantibodies during CMV infection role of CMV reactivation in the regulation of auto production may be based on a number of possible mechanisms. Autoantigens was shown in a study of SLE patients with CMV IgG antibodies. The present on the surface of cells following CMV infection. One described authors identified differential production of antibodies to U1 RNP/Sm mechanism is that there is an induction of autoantigens on the surface and U1-70K based on the presence of CMV IgM. of cells following CMV infection, and similar cell surface epitopes then induce autoantibodies [13]. Reactivation and immunosuppression CMV infection has also occurred as part of treatment protocols for Systemic Lupus Erythematosis SLE and autoimmune disease. The risk of reactivation of CMV is found in Systemic Lupus Erythematosus or SLE is one of the more frequently approximately 20 % of patients during anti-CD 20 therapy. CMV infection CMV associated autoimmune diseases. In particular, non-renal vascular among SLE patients may be severe and fatal. Some associated risk factors SLE may manifest after CMV infection. It therefore may be useful in the for CMV mortality include cytopenias, prior cyclophosphamide therapy, study of the complex relationship between infection and autoimmunity. multisystem involvement and delayed initiation of antiviral therapy [17]. SLE is characterized by production of specific autoantibodies directed against nuclear proteins. CMV infection has been shown to trigger CMV infection among patients with combined variable the production of autoantibodies and the clinical symptoms of SLE. immunodeficiency (CVID), may be associated with an increased The relationship on a molecular level between CMV infection and the risk for autoimmune disease. This lends further support that among production of autoantibodies is thought to involve the closely linked immunocompromised patients, CMV is a risk factor for the development antibodies of anti-Sm and anti-RNP (ribonucleoprotein), which are of autoimmune disease. Further support for this possible mechanism is that directed to a small family of RNPs that bind to the U series of snRNAs [14]. patients, such as organ transplant patients receiving immunosuppressive Evidence supportive of this mechanism is that among patients with SLE, therapies, have an established risk for CMV reactivation [18]. latent CMV is more detectable among patients with anti-RNP antibodies, The molecular mechanisms of CMV induction of autoimmunity compared to those without anti-RNP antibodies. Anti-RNP antibodies were more frequent in patients with symptomatic CMV infection, than Post-infection autoimmunity may be induced by the following in patients without CMV infection. The primary immune response to molecular mechanisms [10]: CMV is directed to epitopes on the pp65 viral antigen. In normal subjects, Molecular mimicry: This is one of the most likely mechanisms of anti-CMV antibodies are produced and the infection does not lead to autoimmunity following CMV infection. As the name suggests, there is a autoimmune disease. Among patients with SLE, 60% of patients have been crossreactivity between epitopes (i.e. protein, carbohydrate or DNA) shared shown to have IgG anti-pp65 antibodies [14]. by the pathogen and the host. In the host, to establish this mechanism, the Clinical Manifestations of CMV in SLE pathogen must provoke an immune response that crossreacts with host antigen after preceding the development of autoimmune disease. Initiation and exacerbation Epitope switching may occur following protein processing and antigen The clinical presentation of CMV in SLE varies considerably. The most presentation, resulting in an autoimmune response to a novel transformed frequently involved systems included persistent fever, lymphopenias, epitope. anemia and nephrotic syndrome. Both a higher and higher IgG CMV titers are found among SLE patients in comparison with non SLE Bystander activation occurs following viral infection of tissue and autoimmune control patients. Among SLE patients (n=28) who tested subsequent release of sequestered antigen, which activates autoreactive positive for CMV pp65 viral antigen, multivariate analysis revealed an lymphocytes, not involved in the early reaction to viral infection. odds ratio of 6.71, p=0.028, of having lymphopenia ( less than 700/cubic Persistent infection may result in a combination of mono and polyclonal mm). The median SLEDAI score was 10, with a range of 3-27. This study antibodies. demonstrated that among those patients with lymphopenia, CMV viral load was also observed. In addition, this study demonstrated a specific Conclusion correlation between CMV antigenemia and the development of CMV In conclusion, there are multiple mechanisms of SLE pathogenesis, disease among the SLE patients studied.It is also possible that the infection and viral infection of host cells may lead to specific pathways of disease itself may initiate autoimmune disease in non-SLE autoimmune diseases initiation and clinical worsening. SLE is a polygenic multifactorial such as rheumatoid arthritis [15]. One example of CMV as a trigger for disease in which there is heterogeneity in its phenotypic presentation. SLE onset is described in a case report of a 43 year old individual with Viral infections may initiate and amplify autoimmune disease. Microbial CMV and no prior history of systemicillness [16]. peptides with limited sequences have also been shown to lead to the In the study by Su et al. [15] there were 87 SLE patients studied. There autoimmune response. Further studies are needed to elucidate the cellular were positive levels of anti-CMV IgG (97.7%) and the prevalence of and molecular pathways and their interactions with host susceptibility positive anti-CMV IgM in the SLE group was 10.3% (9/87) compared with and genotype.

Citation: Dosanjh A (2016) Cytomegalovirus (CMV) Infection: A Role in the Pathogenesis of Systemic Lupus Erythematosis (SLE). Autoimmun Infec Dis 2(3): doi http://dx.doi.org/10.16966/2470-1025.115

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SciForschenOpen HUB for Scientific Research Open Access References 10. Rosenblyum F, Allen U, Silverman E, Levy D (2013) Cytomegalovirus infection in childhood-onset of systemic lupus erythematosus. Int J 1. Bizarro N, Harel M, Shoenfeld Y (2014) Predictive Autoantibodies In: Clin Rheumatol 8: 137-146. Yehuda Shoenfeld (3rd Eds) Autoantibodies, chapter 7, Elsevier 17. 11. Knight A, Weiss P, Morales K, Gerdes M, Rearson M, et al. (2015) 2. Esposito S, Bosis S, Semino M, Rigante D (2014) Infections and Identifying Differences in Risk Factors for Depression and Anxiety in Systemic Lupus Erythematosus. Eur Clin Microbiol Infect Dis 33: Pediatric Chronic Disease: A Matched Cross-Sectional Study of Youth 1467-1475. with Lupus/Mixed Connective Tissue Disease and Their Peers with . J Pediatr 167: 1397-1403. 3. Halenius A, Hengel H (2014) Human cytomegalovirus and autoimmune disease. Biomed Res Int 42: 1-18. 12. Liu Y, Yin H, Zhao M, Lu Q (2014) TLR2 and TLR 4 in autoimmune disease: A Comprehensive Review. Clin Rev Allergy Immunol 47: 136- 4. Chavele KM, Ehrenstein MR (2011) Regulatory T cells in systemic 147. lupus erythematosus and rheumatoid arthritis. FEBS let 585: 3603-3610. 13. Esposito S, Bosis S, Semino M, Rigante D (2014) Infections and 5. Hom G, Graham RR, Modrek B, Taylor KE, Ortmann W, et al. (2008) systemic lupus erythematosus. Eur J Clin Microbiol Infect Dis 33: Association of SLE with C8orf13-BLK and ITGAM-ITGAX. N Engl J 1467-1475. Med 358: 900-909. 14. Newkirk M, Venrooij W and Marshall G (2001) Autoimmune response to U1 small nuclear ribonucleoprotein (U1snRNP) associated with 6. Fujimoto D, Matsushima A, Nagao M, Takakura S, Ichiyama S (2013) cytomegalovirus infection. Arthritis Res 3: 253-258. Risk factors associated with elevated cytomegalovirus pp65 antigen levels in apteinst with autoimmune disease. Mod Rheumatol 15. Su BY, Su CY, Yu SF, Chen CJ (2007) Incidental discovery of high 23: 345-350. systemic lupus erythematosus disease activity associated with CMV viral activity. Med Microbiol Immunol 196: 165-170. 7. Chisten U, von Herrath M (2005) Infections and Autoimmunity-Good or Bad? J Immunol 174: 7481-7486. 16. Perez-Mercado AE, Vila-Perez S (2010) Cytomegalovirus as a Trigger for SLE. J Clin Rheumatol 16: 335-337. 8. Thewissen M, Somers V, Hellings N, Fraussen J, Damoiseaux J, et 17. Takizawa Y, Inokuma S, Tanaka Y, Saito K, Atsumi T, et al. (2008) al. (2007) CD4+CD28 null T cells in autoimmune disease: pathogenic Clinical characteristics of CMV infection in rheumatic diseases: features and decreased susceptibility to immunoregulation. J Immunol multicenter survey in a large patient population. Rheumatology Oxford 179: 6514-6523. 47: 1373-1378. 9. Chavele KM, Ehrenstein MR (2011) Regulatory T cells in systemic 18. Varani S, Landini MP (2011) Cytomegalovirus-induced lupus erythematosus and rheumatoid arthritis. FEBS Lett 585: 3603- immunopathology and its clinical consequences. Herpesviradae 26: 3610. 2-6.

Citation: Dosanjh A (2016) Cytomegalovirus (CMV) Infection: A Role in the Pathogenesis of Systemic Lupus Erythematosis (SLE). Autoimmun Infec Dis 2(3): doi http://dx.doi.org/10.16966/2470-1025.115

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